Anti-brolucizumab immune response as one prerequisite for rare retinal vasculitis/retinal vascular occlusion adverse events.

In October 2019, Novartis launched brolucizumab, a single-chain variable fragment molecule targeting vascular endothelial growth factor A, for the treatment of neovascular age-related macular degeneration. In 2020, rare cases of retinal vasculitis and/or retinal vascular occlusion (RV/RO) were reported, often during the first few months after treatment initiation, consistent with a possible immunologic pathobiology. This finding was inconsistent with preclinical studies in cynomolgus monkeys that demonstrated no drug-related intraocular inflammation, or RV/RO, despite the presence of preexisting and treatment-emergent antidrug antibodies (ADAs) in some animals. In this study, the immune response against brolucizumab in humans was assessed using samples from clinical trials and clinical practice. In the brolucizumab-naïve population, anti-brolucizumab ADA responses were detected before any treatment, which was supported by the finding that healthy donors can harbor brolucizumab-specific B cells. This suggested prior exposure of the immune system to proteins with structural similarity. Experiments on samples showed that naïve and brolucizumab-treated ADA-positive patients developed a class-switched, high-affinity immune response, with several linear epitopes being recognized by ADAs. Only patients with RV/RO showed a meaningful T cell response upon recall with brolucizumab. Further studies in cynomolgus monkeys preimmunized against brolucizumab with adjuvant followed by intravitreal brolucizumab challenge demonstrated that high ADA titers were required to generate ocular inflammation and vasculitis/vascular thrombosis, comparable to RV/RO in humans. Immunogenicity therefore seems to be a prerequisite to develop RV/RO. However, because only 2.1% of patients with ADA develop RV/RO, additional factors must play a role in the development of RV/RO.

A root cause analysis to identify the mechanistic drivers of immunogenicity against the anti-VEGF biotherapeutic brolucizumab.

Immunogenicity against intravitreally administered brolucizumab has been previously described and associated with cases of severe intraocular inflammation, including retinal vasculitis/retinal vascular occlusion (RV/RO). The presence of antidrug antibodies (ADAs) in these patients led to the initial hypothesis that immune complexes could be key mediators. Although the formation of ADAs and immune complexes may be a prerequisite, other factors likely contribute to some patients having RV/RO, whereas the vast majority do not. To identify and characterize the mechanistic drivers underlying the immunogenicity of brolucizumab and the consequence of subsequent ADA-induced immune complex formation, a translational approach was performed to bridge physicochemical characterization, structural modeling, sequence analysis, immunological assays, and a quantitative systems pharmacology model that mimics physiological conditions within the eye. This approach revealed that multiple factors contributed to the increased immunogenic potential of brolucizumab, including a linear epitope shared with bacteria, non-natural surfaces due to the single-chain variable fragment format, and non-native drug species that may form over prolonged time in the eye. Consideration of intraocular drug pharmacology and disease state in a quantitative systems pharmacology model suggested that immune complexes could form at immunologically relevant concentrations modulated by dose intensity. Assays using circulating immune cells from treated patients or treatment-naïve healthy volunteers revealed the capacity of immune complexes to trigger cellular responses such as enhanced antigen presentation, platelet aggregation, endothelial cell activation, and cytokine release. Together, these studies informed a mechanistic understanding of the clinically observed immunogenicity of brolucizumab and associated cases of RV/RO.

Manifestations of intraocular inflammation over time in patients on brolucizumab for neovascular AMD.

PURPOSE: To describe the adverse events associated with brolucizumab, in particular the sequence of intraocular inflammation (IOI), retinal vasculitis (RV), and/or retinal vascular occlusion (RO). METHODS: This was an unmasked post hoc analysis of the randomized HAWK/HARRIER clinical trials. Patients with neovascular AMD in the brolucizumab arms of the trials were included. IOI-related adverse events reported by study investigators were analyzed to determine early signs and the time course of IOI-related adverse events, using a subgroup of patients with definite/probable IOI cases identified in an independent unmasked post hoc review by an external safety review committee. A limited literature review on IOI following anti-VEGF therapy was also conducted. RESULTS: Among 50 patients with definite/probable IOI cases identified by the safety review committee, 12 had RV or RO adverse events reported by the investigators. For 6 of 12, IOI (other than RV) was reported before RV or RO. The duration from the first IOI adverse event to the first RV or RO adverse event ranged from 16 to 171 days for 5 patients and was 553 days for 1 patient. Four of the 6 patients received ≥ 1 brolucizumab injection on or after the date of the first IOI adverse event and before the first RV or RO adverse event. CONCLUSIONS: IOI may precede RV or RO in some patients treated with brolucizumab.

Pharmacokinetic Interaction Between Fingolimod and Carbamazepine in Healthy Subjects.

This open-label, single-sequence study in healthy subjects investigated the effects of steady-state carbamazepine on the pharmacokinetic (PK) profile of a single 2-mg dose of fingolimod. In period 1, a single oral dose of fingolimod 2 mg (day 1) was followed by PK and safety assessments up to 36 days. In period 2, carbamazepine was administered in flexible, up-titrated doses (600 mg twice daily maximum) for 49 days. Fingolimod was administered on day 35, followed by a study completion evaluation (day 71). The PK analysis included 23 of 26 of the enrolled subjects (88.5%). Coadministration of fingolimod at steady-state carbamazepine concentrations resulted in increased fingolimod CL/F by 67% through the induction of CYP3A4, a cytochrome with negligible involvement in fingolimod clearance in an uninduced state. Fingolimod Cmax was reduced by 18% and AUCinf by 40%, as was T1/2 (106 vs 163 hours). A similar trend was observed for fingolimod-P. Models linking fingolimod-P blood concentrations to lymphocyte count or annual relapse rate suggest that such a decrease would have a low impact on the treatment effect. However, in the absence of efficacy data of fingolimod at doses lower than the therapeutic dose, their coadministration should be used with caution.

Determination of Seminal Concentration of Fingolimod and Fingolimod-Phosphate in Multiple Sclerosis Patients Receiving Chronic Treatment With Fingolimod.

The safety profile of fingolimod 0.5 mg, approved therapy for relapsing multiple sclerosis, is well established in clinical and real-world studies. As fingolimod is teratogenic in rats, it was considered important to assess the concentrations of fingolimod and its active metabolite, fingolimod-phosphate, in the semen of male patients on treatment and the risk of harming a fetus in a pregnant partner. In this multicenter open-label study, 13 male patients receiving fingolimod for at least 6 months provided 1 semen and 1 blood sample for analyte concentration measurements. The steady-state seminal concentrations of fingolimod and fingolimod-phosphate were close to those simultaneously observed in blood. The amount of fingolimod-related material in 10 mL of ejaculate was estimated to be 47.5 ng. The estimated fingolimod and fingolimod-phosphate blood Cmax values in a woman having regular sexual intercourse with a male patient treated with fingolimod 0.5 mg were approximately 400 and 2400 times smaller than the estimated values in the embryo-fetal development study in rats at the no-observed-adverse-event level. Consequently, the risk of harming a fetus in a pregnant woman is considered extremely unlikely.

Can Disproportionality Analysis of Post-marketing Case Reports be Used for Comparison of Drug Safety Profiles?

Clinical trials usually do not have the power to detect rare adverse drug reactions. Spontaneous adverse reaction reports as for example available in post-marketing safety databases such as the FDA Adverse Event Reporting System (FAERS) are therefore a valuable source of information to detect new safety signals early. To screen such large data-volumes for safety signals, data-mining algorithms based on the concept of disproportionality have been developed. Because disproportionality analysis is based on spontaneous reports submitted for a large number of drugs and adverse event types, one might consider using these data to compare safety profiles across drugs. In fact, recent publications have promoted this practice, claiming to provide guidance on treatment decisions to healthcare decision makers. In this article we investigate the validity of this approach. We argue that disproportionality cannot be used for comparative drug safety analysis beyond basic hypothesis generation because measures of disproportionality are: (1) missing the incidence denominators, (2) subject to severe reporting bias, and (3) not adjusted for confounding. Hypotheses generated by disproportionality analyses must be investigated by more robust methods before they can be allowed to influence clinical decisions.

Pharmacokinetics of fingolimod and metabolites in subjects with severe renal impairment: An open-label, single-dose, parallel-group study.

OBJECTIVE: This study assessed the pharmacokinetics and tolerability of fingolimod and its metabolites in severe renal impairment and healthy subjects. METHODS: In this single-dose, open-label study, 9 severe renal impairment subjects and 9 demographically matched healthy subjects were included. Each subject received a single oral dose of fingolimod 1.25 mg, and their blood and urine samples were assessed. The pharmacokinetics of fingolimod and its metabolites, fingolimod-phosphate (active metabolite, fingolimod-P), M2, and M3, were compared in both groups. Safety and tolerability were also assessed. RESULTS: In severe renal impairment subjects, mean±standard deviation values of Cmax (ng/mL) of fingolimod and fingolimod-P were 0.878±0.256 and 1.13±0.293 vs. 0.653±0.138 and 0.904±0.229 in healthy subjects, respectively. The overall drug exposures (AUCinf (ngxh/mL)) for fingolimod and fingolimod-P were 131±90.7 and 75.5±33.6 in severe renal impairment subjects vs. 82.3±36.9 and 65.9±30.6 in healthy subjects, respectively. t1/2 (hours) for fingolimod and fingolimod-P was comparable in severe renal impairment subjects (94±53 and 95±50) and healthy subjects (85±25 and 101±46). All adverse events were as expected for fingolimod 1.25 mg. CONCLUSIONS: The exposure to fingolimod and fingolimod-P was moderately increased (90% CI, 0.94-2.18) in severe renal impairment subjects, while half-lives and protein binding were similar to those in healthy subjects. Given that these changes are not clinically meaningful, fingolimod dose adjustment is considered unnecessary in patients with mild, moderate, or severe renal impairment.

Effect of fingolimod (FTY720) on cerebral blood flow, platelet function and macular thickness in healthy volunteers.

AIM: Fingolimod, a sphingosine 1-phosphate receptor modulator, is the first oral disease modifying therapy approved for the treatment of relapsing multiple sclerosis. The aim of this double-blind, placebo-controlled study was to evaluate the effect of fingolimod on cerebral blood flow, platelet function and macular thickness in healthy volunteers. METHODS: The study included 88 healthy volunteers who received fingolimod 0.5 mg or 1.25 mg or matched placebo over a period of 4 weeks. Transcranial colour coded sonography was performed to measure mean blood flow velocities, the platelet function was measured by the PFA-100® assay using a collagen/epinephrine cartridge and macular thickness was measured using optical coherence tomography. An assessment of non-inferiority of fingolimod vs. placebo was performed against a reference value (20% of the overall baseline value). RESULTS: All 88 randomized participants completed the study. At day 28 compared with baseline value, for 0.5 mg, 1.25 mg and placebo treatments, the mean middle cerebral artery blood flow velocity decreased by 4, 1 and 3.7 cm s(-1), respectively. The platelet function analyzer closure time increase was not significant (7.8, 7.5 and 10.4 s, respectively). The mean percentage change in the central foveal thickness from baseline for both eyes was below 3% for all groups. The safety profile of fingolimod in this study was found consistent with the previous reports. CONCLUSIONS: In healthy volunteers, the changes seen with both fingolimod doses were found to be within normal variability, non-inferior and comparable with those observed with placebo for all the pharmacodynamic parameters assessed.

Tolerability and Pulmonary Pharmacodynamic Effects During Treatment Initiation of Once-Daily Oral Fingolimod in Subjects With Moderate Asthma.

Fingolimod, a first-in-class sphingosine 1-phosphate receptor modulator, is the first approved oral therapy for relapsing multiple sclerosis (MS). While treatment initiation of clinical dose of fingolimod (0.5 mg) does not affect pulmonary function, supra-therapeutic doses (≥5.0 mg) increased airway resistance. The aim of this double-blind, placebo-controlled, parallel group, 10-day study was to measure the effect of fingolimod on pulmonary function in otherwise healthy patients with moderate asthma. Subjects (n = 36) were randomized into four cohorts that received either fingolimod 0.5, 1.25, 2.5 mg, or placebo once daily for 10 days. Subjects in placebo and fingolimod 0.5 mg groups did not differ in FEV1 AUEC0-6 h , FEF25-75% AUEC0-6 h , or in short-acting beta (ß) 2 agonists (SABA, rescue bronchodilator) use. Subjects on higher doses of fingolimod showed a mild reduction in FEV1 AUEC0-6 h and FEF25-75% AUEC0-6 h and a significant sixfold increase in SABA use versus placebo. One subject had moderately severe, acute exacerbation of asthma after receiving the first dose of fingolimod 1.25 mg that quickly responded to inhaled SABA. The observed safety profile was consistent with previous reports. These results provide reassurance that moderately asthmatic MS individuals can start on fingolimod 0.5 mg therapy with minimal effects on pulmonary function and SABA use.

Chronopharmacokinetics of mycophenolic acid and its glucuronide and acyl glucuronide metabolites in kidney transplant recipients converted from cyclosporine to everolimus.

BACKGROUND: The influence of the conversion from cyclosporine (CsA) to everolimus (EVR) on the chronopharmacokinetics of mycophenolic acid (MPA) and its glucuronide (MPAG) and acyl glucuronide (acyl-MPAG) metabolites in patients receiving enteric-coated mycophenolate sodium (EC-MPS) has not been studied. METHODS: We evaluated daytime and nighttime steady-state MPA, MPAG, and acyl-MPAG pharmacokinetics in 24 stable kidney transplant recipients while receiving cyclosporine and 28 days after conversion from CsA to EVR. The effect of concomitant treatment and the circadian difference on AUC(t,ss) and C(max,ss) were assessed using a linear mixed model. RESULTS: After conversion from CsA to EVR, MPA AUC(t,ss) was 43% higher (29% daytime and 58% during nighttime), whereas MPAG AUC(t,ss) was 33% lower (35% daytime and 30% during nighttime) and acyl-MPAG AUC(t,ss) was 31% lower (36% during daytime and 26% nighttime). Compared with daytime, MPA AUC(t,ss) was 25% lower (32% with CsA and 17% with EVR), MPAG AUC(t,ss) was 24% lower (26% with CsA and 21% with EVR), and acyl-MPAG AUC(t,ss) was 26% lower (32% with CsA and 21% with EVR) during nighttime. After conversion from CsA to EVR, MPAG:MPA and acyl-MPAG:MPA AUC(t,ss) ratios were 50% lower but were not different during daytime compared with nighttime EC-MPS administration. There was no correlation between CsA or EVR concentrations with MPA, MPAG, and acyl-MPAG exposures during daytime and nighttime. At least 1 adverse event was reported in 70.8% of patients receiving EC-MPS and CsA and in 91.7% receiving EC-MPS and EVR. CONCLUSION: In stable kidney transplant recipients receiving EC-MPS and steroids, exposures to MPA, MPAG, and acyl-MPAG were lower during nighttime compared with daytime, both with CsA or EVR. This circadian effect on MPA exposure did not correlate with CsA or EVR concentrations or with altered MPAG and acyl-MPAG formation.

Pharmacokinetics of fingolimod (FTY720) and a combined oral contraceptive coadministered in healthy women: drug-drug interaction study results.

BACKGROUND: Fingolimod has a novel mechanism of action in multiple sclerosis, being a first-in-class sphingosine 1-phosphate receptor modulator. Because of a potential risk of fetal toxicity based on animal studies, women of childbearing potential are advised to take effective contraceptive measures during and for 2 months after stopping fingolimod therapy. To assess whether the efficacy of a combined oral contraceptive (OC) could be compromised during fingolimod therapy, a steady-state, drug-drug interaction study of fingolimod with ethinylestradiol/levonorgestrel was performed in healthy female volunteers. OBJECTIVE: To assess the interaction between fingolimod 0.5 mg once daily and ethinylestradiol 30 µg/ levonorgestrel 150 µg once daily at a steady state. METHODS: 31 healthy women received the combined OC only on Days 1 - 14, followed by OC plus fingolimod on Days 15 - 28. RESULTS: In the presence of fingolimod, ethinylestradiol pharmacokinetics were unchanged, and levonorgestrel maximum plasma concentration at steady state and area under the concentration-time curve during a dosing interval increased by factors of 1.10 (90% CI 1.05 - 1.16) and 1.22 (90% CI 1.18 - 1.27), respectively. CONCLUSIONS: Fingolimod therapy does not alter the pharmacokinetics of the combined OC ethinylestradiol/ levonorgestrel to a clinically significant degree. Ethinylestradiol/levonorgestrel does not alter the pharmacokinetics of fingolimod. Women receiving fingolimod therapy are able to use a combined OC as a means of effective birth control.

Clinical pharmacokinetics of fingolimod.

Fingolimod (FTY720), a sphingosine 1-phosphate receptor modulator, is the first in a new class of therapeutic compounds and is the first oral therapy approved for the treatment of relapsing forms of multiple sclerosis (MS). Fingolimod is a structural analogue of endogenous sphingosine and undergoes phosphorylation to produce fingolimod phosphate, the active moiety. Fingolimod targets MS via effects on the immune system, and evidence from animal models indicates that it may also have actions in the central nervous system. In phase III studies in patients with relapsing-remitting MS, fingolimod has demonstrated efficacy superior to that of an approved first-line therapy, intramuscular interferon-ß-1a, as well as placebo, with benefits extending across clinical and magnetic resonance imaging measures. The pharmacokinetic profiles of fingolimod and fingolimod phosphate have been extensively investigated in studies in healthy volunteers, renal transplant recipients (the indication for which fingolimod was initially under clinical development, but the development was subsequently discontinued) and MS patients. Results from these studies have demonstrated that fingolimod is efficiently absorbed, with an oral bioavailability of >90%, and its absorption is unaffected by dietary intake, therefore it can be taken without regard to meals. Fingolimod and fingolimod phosphate have a half-life of 6-9 days, and steady-state pharmacokinetics are reached after 1-2 months of daily dosing. The long half-life of fingolimod, together with its slow absorption, means that fingolimod has a flat concentration profile over time with once-daily dosing. Fingolimod and fingolimod phosphate show dose-proportional exposure in single- and multiple-dose studies over a range of 0.125-5 mg; hence, there is a predictable relationship between dose and systemic exposure. Furthermore, fingolimod and fingolimod phosphate exhibit low to moderate intersubject pharmacokinetic variability. Fingolimod is extensively metabolized, with biotransformation occurring via three main pathways: (i) reversible phosphorylation to fingolimod phosphate; (ii) hydroxylation and oxidation to yield a series of inactive carboxylic acid metabolites; and (iii) formation of non-polar ceramides. Fingolimod is largely cleared through metabolism by cytochrome P450 (CYP) 4F2. Since few drugs are metabolized by CYP4F2, fingolimod would be expected to have a relatively low potential for drug-drug interactions. This is supported by data from in vitro studies indicating that fingolimod and fingolimod phosphate have little or no capacity to inhibit and no capacity to induce other major drug-metabolizing CYP enzymes at therapeutically relevant steady-state blood concentrations. Population pharmacokinetic evaluations indicate that CYP3A inhibitors and CYP3A inducers have no effect or only a weak effect on the pharmacokinetics of fingolimod and fingolimod phosphate. However, blood concentrations of fingolimod and fingolimod phosphate are increased moderately when fingolimod is coadministered with ketoconazole, an inhibitor of CYP4F2. The pharmacokinetics of fingolimod are unaffected by renal impairment or mild-to-moderate hepatic impairment. However, exposure to fingolimod is increased in patients with severe hepatic impairment. No clinically relevant effects of age, sex or ethnicity on the pharmacokinetics of fingolimod have been observed. Fingolimod is thus a promising new therapy for eligible patients with MS, with a predictable pharmacokinetic profile that allows effective once-daily oral dosing.

Pharmacodynamic effects of steady-state fingolimod on antibody response in healthy volunteers: a 4-week, randomized, placebo-controlled, parallel-group, multiple-dose study.

Fingolimod, a first-in-class oral sphingosine 1-phosphate receptor (S1PR) modulator, is approved in many countries for relapsing-remitting multiple sclerosis, at a once-daily 0.5-mg dose. A reduction in peripheral lymphocyte count is an expected consequence of the fingolimod mechanism of S1PR modulation. The authors investigated if this pharmacodynamic effect impacts humoral and cellular immunogenicity. In this double-blind, parallel-group, 4-week study, 72 healthy volunteers were randomized to steady state, fingolimod 0.5 mg, 1.25 mg, or to placebo. The authors compared T-cell dependent and independent responses to the neoantigens, keyhole limpet hemocyanin (KLH), and pneumococcal polysaccharides vaccine (PPV-23), respectively, and additionally recall antigen response (tetanus toxoid [TT]) and delayed-type hypersensitivity (DTH) to KLH, TT, and Candida albicans. Fingolimod caused mild to moderate decreases in anti-KLH and anti-PPV-23 IgG and IgM levels versus placebo. Responder rates were identical between placebo and 0.5-mg groups for anti-KLH IgG (both > 90%) and comparable for anti-PPV-23 IgG (55% and 41%, respectively). Fingolimod did not affect anti-TT immunogenicity, and DTH response did not differ between placebo and fingolimod 0.5-mg groups. Expectedly, lymphocyte count reduced substantially in the fingolimod groups versus placebo but reversed by study end. Fingolimod was well tolerated, and the observed safety profile was consistent with previous reports.

Placebo-controlled study of the effects of fingolimod on cardiac rate and rhythm and pulmonary function in healthy volunteers.

PURPOSE: Fingolimod (FTY720) is a sphingosine-1 phosphate-receptor (S1PR) modulator recently approved as a once-daily oral therapy for relapsing multiple sclerosis (MS) in many countries. As S1PRs are widely expressed, including in heart and lung tissues, this study investigated the possible effects of fingolimod on heart-rate circadian rhythm and pulmonary function. METHODS: Healthy volunteers (n = 39) were randomized to receive fingolimod 0.5 mg, 1.25 mg, or placebo for 14 days. Heart rate and measures of cardiac and pulmonary function were assessed during the study. RESULTS: Mean heart rate for the first 12 h postdose was lower for both fingolimod than for placebo groups (p < 0.001) and remained 10-15 bpm lower than placebo until day 14 (p < 0.05). Heart rate circadian rhythm, cardiac output, stroke volume, and systemic vascular resistance were similar among treatment groups throughout the study. There was no evidence of an effect of fingolimod on pulmonary function. Absolute lymphocyte counts decreased by approximately 70% from baseline in both fingolimod groups (day 14) and began to increase within 14 days of stopping treatment. CONCLUSIONS: In healthy volunteers treated for 14 days, once-daily fingolimod doses of 0.5 mg and 1.25 mg had no effect on cardiac or pulmonary function beyond a transient decrease in heart rate at treatment initiation.

Population pharmacokinetics of fingolimod phosphate in healthy participants.

Fingolimod (FTY720) is a sphingosine 1-phosphate receptor (S1PR) modulator currently being evaluated for the treatment of multiple sclerosis. Fingolimod undergoes phosphorylation in vivo to yield fingolimod phosphate (fingolimod-P), which modulates S1PRs expressed on lymphocytes and cells in the central nervous system. The authors developed a population model, using pooled data from 7 phase 1 studies, to enable characterization of fingolimod-P pharmacokinetics following oral administration of fingolimod and to evaluate the impact of key demographic variables on exposure. The fingolimod-P concentration-time course after either single or multiple doses of fingolimod was described by a 2-compartment model with first-order apparent formation and elimination, lag time in the apparent formation, and dose-dependent relative bioavailability and apparent central volume of distribution. Body weight and ethnicity were identified as demographic covariates correlated with the disposition of fingolimod-P. Model predictions indicated no need for dose adjustment of fingolimod based on body weight; the effect of ethnicity on the disposition of fingolimod requires further investigation. The accurate prediction of the pharmacokinetic profile of fingolimod-P determined empirically in 2 large phase 3 trials provides external validation of the model.

Fingolimod (FTY720): discovery and development of an oral drug to treat multiple sclerosis.

The discovery of fingolimod (FTY720/Gilenya; Novartis), an orally active immunomodulatory drug, has opened up new approaches to the treatment of multiple sclerosis, the most common inflammatory disorder of the central nervous system. Elucidation of the effects of fingolimod--mediated by the modulation of sphingosine 1-phosphate (S1P) receptors--has indicated that its therapeutic activity could be due to regulation of the migration of selected lymphocyte subsets into the central nervous system and direct effects on neural cells, particularly astrocytes. An improved understanding of the biology of S1P receptors has also been gained. This article describes the discovery and development of fingolimod, which was approved by the US Food and Drug Administration in September 2010 as a first-line treatment for relapsing forms of multiple sclerosis, thereby becoming the first oral disease-modifying therapy to be approved for multiple sclerosis in the United States.

Randomized crossover study to assess the inter- and intrasubject variability of morning mycophenolic acid concentrations from enteric-coated mycophenolate sodium and mycophenolate mofetil in stable renal transplant recipients.

The delayed release of mycophenolic acid (MPA) from enteric-coated mycophenolate sodium (EC-MPS, myfortic®) may have an impact on the variability of MPA trough (C0 h) levels. A randomized, two-period crossover study was performed in 24 maintenance renal transplants to evaluate the inter- and intrasubject variability of MPA predose levels from EC-MPS and mycophenolate mofetil (MMF, CellCept®), both in combination with cyclosporine. Patients received EC-MPS (720 mg b.i.d.) and MMF (1000 mg b.i.d.) for a period of 21 d each. MPA plasma levels were measured over the final seven consecutive days at -1, 0, 1, 2, and 3 h after the morning MPA dose. Intersubject coefficients of variation (%CV) for MPA troughs were 47.5% (95% CI, 34.1-80.3) and 54.4% (40.0-86.8) for EC-MPS and MMF, respectively; intrasubject %CVs were 62.7% (55.1-72.9) and 42.8% (37.9-49.2). High MPA C0 h levels>10 µg/mL were rarely observed with both EC-MPS (1.8%) and MMF (0.6%). Mean MPA area under the curve (AUC)0-3 h was comparable between treatments, while MPA C0 h was on average 46% higher with EC-MPS. In conclusion, predose MPA trough level monitoring appears of limited value during EC-MPS and MMF therapy given the large intrasubject variability in MPA C0 h levels with both treatments.

Ketoconazole increases fingolimod blood levels in a drug interaction via CYP4F2 inhibition.

The sphingosine-1-phosphate receptor modulator fingolimod is predominantly hydroxylated by cytochrome CYP4F2. In vitro experiments showed that ketoconazole significantly inhibited the oxidative metabolism of fingolimod by human liver microsomes and by recombinant CYP4F2. The authors used ketoconazole as a putative CYP4F2 inhibitor to quantify its influence on fingolimod pharmacokinetics in healthy subjects. In a 2-period, single-sequence, crossover study, 22 healthy subjects received a single 5-mg dose of fingolimod in period 1. In period 2, subjects received ketoconazole 200 mg twice daily for 9 days and a single 5-mg dose of fingolimod coadministered on the 4th day of ketoconazole treatment. Ketoconazole did not affect fingolimod t(max) or half-life, but there was a weak average increase in C(max) of 1.22-fold (90% confidence interval, 1.15-1.30). The AUC over the 5 days of ketoconazole coadministration increased 1.40-fold (1.31-1.50), and the full AUC to infinity increased 1.71-fold (1.53-1.91). The AUC of the active metabolite fingolimod-phosphate was increased to a similar extent by 1.67-fold (1.50-1.85). Ketoconazole predose plasma levels were not altered by fingolimod. The magnitude of this interaction suggests that a proactive dose reduction of fingolimod is not necessary when adding ketoconazole to a fingolimod regimen. The clinician, however, should be aware of this interaction and bear in mind the possibility of a fingolimod dose reduction based on clinical monitoring.

The ability of atropine to prevent and reverse the negative chronotropic effect of fingolimod in healthy subjects.

AIMS: The authors determined whether intravenous atropine can prevent or counteract the negative chronotropic effect of the immunomodulator fingolimod. METHODS: In this randomized, placebo-controlled, two-period, crossover study, 12 healthy subjects received 5 mg fingolimod orally concurrently with intravenous atropine (titrated to a heart rate of 110-120 beats min(-1)) or intravenous placebo. A second group of 12 subjects received atropine/placebo 4 h after the fingolimod dose. Continuous telemetry measurements were made for 24 h after each fingolimod dose. RESULTS: Fingolimod administration alone yielded a heart rate nadir of 51 +/- 5 beats min(-1) at a median 4 h postdose with heart rate remaining depressed at 51-64 beats min(-1) over the rest of the day. Concurrent administration of fingolimod and atropine yielded a nadir of 66 +/- 6 beats min(-1) resulting in an atropine: placebo ratio (90% confidence interval) of 1.30 (1.22, 1.36). When atropine was administered at the time of the nadir, it was able to reverse the negative chronotropic effect of fingolimod from a heart rate of 56 +/- 9 beats min(-1) (placebo) to 64 +/- 8 beats min(-1) (atropine) resulting in an atropine: placebo ratio of 1.15 (1.04, 1.26). Atropine had no influence on the pharmacokinetics of fingolimod. CONCLUSIONS: Atropine administered concurrently with fingolimod prevented the heart rate nadir that typically occurs 4 h postdose. Atropine administered at the time of the heart rate nadir was able to reverse the negative chronotropic effect of fingolimod.